Thyroid Function Testing During Pregnancy

Thyroid function tests are frequently ordered during pregnancy. Normal pregnancy is associated with an increase in renal iodine excretion, an increase in thyroxine binding proteins, an increase in thyroid hormone production, and thyroid stimulatory effects of hCG. In iodine replete countries, the thyroid gland increases in size by 10% and production of thyroxine (T4) and triiodinethyronine (T3) increase by nearly 50%.

As a result of these physiologic changes, thyroid function tests of healthy pregnant women differ from those of healthy nonpregnant women. Consequently the reference ranges for TSH and fT4 are different. In 2017, the American Thyroid Association published revised guidelines for the diagnosis and management of thyroid disease during pregnancy and the postpartum.

TSH reference range shifts downward during pregnancy. The magnitude of the downward shift is even greater in twin pregnancies. The largest decrease in serum TSH is observed during the first trimester because of elevated levels of serum hCG directly stimulating the TSH receptor and thereby increasing thyroid hormone production. Thereafter, serum TSH and its reference range gradually rise in the second and third trimesters, but remain lower than in nonpregnant women. In the first trimester, the lower reference range of TSH can be reduced by approximately 0.4 mU/L, while the upper reference range is reduced by approximately 0.5 mU/L. For the typical patient in early pregnancy, this corresponds to a TSH upper reference limit of 4.0 mU/L. This reference limit should generally be applied beginning with the late first trimester, weeks 7 to12, with a gradual return towards the nonpregnant range in the second and third trimesters.

Unbound T4 represents only about 0.03% of the total T4 content in plasma. Total T4 concentrations are measured in the nanomoles, while FT4 concentrations are measured in the picomoles. Accurately measuring FT4 in the presence of high concentrations of bound T4 is challenging, especially with the increase of thyroxine binding globulin during pregnancy. High protein concentrations in serum samples tend to result in higher FT4 values. The ATA recognized that automated indirect analog immunoassays for fT4 may be inaccurate during pregnancy. In contrast, measurement of total T4 and the calculated FT4 index do show the expected inverse relationship with TSH. ATA recommends using a pregnancy-adjusted total T4 measurement or free thyroxine index whenever possible.

Changes in total T4 concentration during pregnancy are predictable, with an increase from weeks 7 to 16 of gestation, ultimately reaching approximately 50% above the nonpregnant level. This level is sustained throughout the remainder of pregnancy. The upper limit of the reference range can be calculated by shifting the nonpregnant limit 50% higher. This limit can be applied after week 16 of gestation. If a T4 measurement is required before then, the upper reference range can be calculated by increasing the nonpregnant upper reference limit by 5% per week, beginning with week 7.

Thyroid antibodies are present in 2 to 17% of pregnant women. The prevalence varies with ethnicity, being higher in Caucasian and Asian women than in African American women. Subclinical hypothyroidism is associated with adverse maternal and fetal outcomes. Euthyroid pregnant women who are positive for thyroid peroxidase (TPO) or thyroglobulin (Tg) antibodies should have TSH measured at the onset of pregnancy and every 4 weeks through midpregnancy.

Women who have subclinical hypothyroidism and are undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) have worse outcomes when TSH is higher than 2.5 mU/L. ATA recommends treatment of these women with levothyroxine to maintain a TSH concentration <2.5 mU/L.

ATA does not recommend for or against universal TSH screening of pregnant women, due to insufficient evidence. All patients seeking pregnancy, or newly pregnant, should undergo clinical evaluation thyroid dysfunction. Patients with risk factors for thyroid disease should be have TSH measured.

Alexander EK et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 2017;27:315-389.